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Ferritin

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Ferritin
Structure of the murine ferritin complex. 1lb3[1]
Identifiers
Symbol?
PfamPF00210
Pfam clanCL0044
InterProIPR008331
SCOP21fha / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
ferritin, light polypeptide
Identifiers
SymbolFTL
NCBI gene2512
HGNC3999
OMIM134790
RefSeqNM_000146
UniProtP02792
Other data
LocusChr. 19 q13.3–13.4
Search for
StructuresSwiss-model
DomainsInterPro
ferritin, heavy polypeptide 1
Identifiers
SymbolFTH1
Alt. symbolsFTHL6
NCBI gene2495
HGNC3976
OMIM134770
RefSeqNM_002032
UniProtP02794
Other data
LocusChr. 11 q13
Search for
StructuresSwiss-model
DomainsInterPro
ferritin mitochondrial
Crystallographic structure of mitochondrial ferritin.[2]
Identifiers
SymbolFTMT
NCBI gene94033
HGNC17345
OMIM608847
RefSeqNM_177478
UniProtQ8N4E7
Other data
LocusChr. 5 q23.1
Search for
StructuresSwiss-model
DomainsInterPro

Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including algae, bacteria, higher plants, and animals. In humans, it acts as a buffer against iron deficiency and iron overload.[3]

Ferritin is a globular protein complex consisting of 24 protein subunits and is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. Ferritin that is not combined with iron is called apoferritin.

Description

Ferritin is a protein of 450 kDa consisting of 24 subunits that is present in every cell type.[4] In vertebrates, these subunits are both the light (L) and the heavy (H) type with an apparent molecular weight of 19 kDA or 21 kDA respectively; their sequences are about 50% homologous.[4] Amphibians have an additional ("M") type of ferritin;[5] the single ferritin of plants and bacteria most closely resembles the vertebrate H-type.[5] Two types have been recovered in the gastropod Lymnaea, the somatic ferritin being distinct from the yolk ferritin (see below).[5] An additional subunit resembling Lymnaea soma ferritin is associated with shell formation in the pearl oyster.[6] Two types are present in the parasite Schistosoma, one in males, the other in females.[5] All the aforementioned ferritins are similar, in terms of their primary sequence, with the vertebrate H-type.[5] In E. coli, a 20% similarity to human H-ferritin is observed.[5] Inside the ferritin shell, iron ions form crystallites together with phosphate and hydroxide ions. The resulting particle is similar to the mineral ferrihydrite. Each ferritin complex can store about 4500 iron (Fe3+) ions.[4][5]

Some ferritin complexes in vertebrates are hetero-oligomers of two highly-related gene products with slightly different physiological properties. The ratio of the two homologous proteins in the complex depends on the relative expression levels of the two genes.

Mitochondrial ferritin was recently identified as a protein precursor, and is classified as a metal-binding protein that is located within the mitochondria.[7] After the protein is taken up by the mitochondria it can be processed into a mature protein and assemble to form functional ferritin shells. Its structure was determined at 1.70 angstroms through the use of X-ray diffraction and contains 182 residues. It is 67% helical. The Ramachandran plot [8] shows that the structure of mitochondrial ferritin is mainly alpha helical with a low prevalence of beta sheets. Unlike other human ferritin, it appears to have no introns in its genetic code.

Genetic structure

In human ferritin, introns are present between the 34/5th,[clarification needed] 82/3rd, and 14/5th amino acid residues; in addition, one to two hundred untranslated bases grace either end of the combined exons.[4] The Tyrosine residue at amino acid position 27 is thought to be associated with biomineralization.[9]

Function

Iron storage

Ferritin serves to store iron in a non-toxic form, to deposit it in a safe form, and to transport it to areas where it is required.[10] The function and structure of the expressed ferritin protein varies in different cell types. This is controlled primarily by how much mRNA is translated, and how stable the mRNA is. mRNA concentration is further tweaked by changes to how it is stored and how efficiently it is transcribed.[4] The presence of iron itself is a major trigger for the production of ferritin,[4] with some exceptions (such as the yolk ferritin of the gastropod Lymnaea, which lacks an iron-responsive unit).[5]

Free iron is toxic to cells as it acts as a catalyst in the formation of free radicals from reactive oxygen species via the Fenton Reaction.[11] Hence vertebrates use an elaborate set of protective mechanisms to bind iron in various tissue compartments. Within cells, iron is stored in a protein complex as ferritin or hemosiderin. Apoferritin binds to free ferrous iron and stores it in the ferric state. As ferritin accumulates within cells of the reticuloendothelial system, protein aggregates are formed as hemosiderin. Iron in ferritin or hemosiderin can be extracted for release by the RE cells although hemosiderin is less readily available. Under steady state conditions, the serum ferritin level correlates with total body iron stores; thus, the serum ferritin FR5Rl is the most convenient laboratory test to estimate iron stores.

Because iron is an important mineral in mineralization, ferritin is employed in the shells of organisms such as molluscs to control the concentration and distribution of iron, thus sculpting shell morphology and colouration.[12][13] It also plays a role in the haemolymph of the polyplacophora where it serves to rapidly transport iron to the mineralizing radula.[14]

Ferroxidase activity

The heavy chain of Ferritin also possesses ferroxidase activity, this involves the conversion of iron from the ferrous (Fe2+) to ferric (Fe 3+) forms. This limits the deleterious reaction which occurs between ferrous iron and hydrogen peroxide known as the Fenton reaction which produces the highly damaging hydroxyl radical.

Immune response

Ferritin concentrations increase drastically in the presence of an infection or cancer; this is necessary to counter the infective agent's attempt to bind iron from the host's tissue.[15] The inflammatory response may cause ferritin to migrate from the plasma to within cells, in order to deny iron to the infective agent.[15]

Stress response

The concentration of ferritin has been shown to increase in response to stresses such as anoxia;[16] this implies that it is an acute phase protein.[17]

Mitochondria

Mitochondrial ferritin has many roles pertaining to molecular function. It participates in ferroxidase activity, binding, iron ion binding, oxidoreductase activity, ferric iron binding, metal ion binding as well as transition metal binding. Within the realm of biological processes it participates in oxidation-reduction, iron ion transport across membranes and cellular iron ion homeostasis.

Yolk

In some snails, the protein component of the egg yolk is primarily ferritin;[18] this is a different ferritin, with a different genetic sequence, from the somatic ferritin. It is produced in the midgut glands and secreted into the haemolymph, hence it is transported to the eggs.[18]

Industrial applications

Ferritin is also used in materials science as a precursor in making iron nanoparticles for carbon nanotube growth by chemical vapor deposition.

Expression

In vertebrates, ferritin is usually found within cells, although it is also present in smaller quantities in the plasma.[15]

Diagnostic uses

Serum ferritin levels are measured in medical laboratories as part of the iron studies workup for anemia and for restless legs syndrome. The ferritin levels measured usually have a direct correlation with the total amount of iron stored in the body. However, ferritin levels may be artificially high in cases of anemia of chronic disease where ferritin is elevated in its capacity as an acute phase protein and not as a marker for iron overload.

Normal Ranges

A normal ferritin blood level, referred to as the reference interval is determined by many testing laboratories. The ranges for ferritin can vary between laboratories but are usually between 30–400 ng/mL (=μg/L) for males, and 15–200 ng/mL (=μg/L) for females.

Low

If the ferritin level is low, there is a risk for lack of iron, which could lead to anemia.

In the setting of anemia, low serum ferritin is the most specific lab test for iron deficiency anemia.[19] However it is less sensitive, since its levels are increased in the blood by infection or any type of chronic inflammation,[20] and these conditions may convert what would otherwise be a low level of ferritin from lack of iron, into a value in the normal range. For this reason, low ferritin levels carry more information than those in the normal range.

Low ferritin may also indicate hypothyroidism, vitamin C deficiency or celiac disease

In adolescents and teenagers, ferritin levels that are low but yet above those causing anemia and sickness (12[21] to 50 ng/mL) may cause symptoms of restless legs syndrome.[22]

A falsely low blood ferritin (equivalent to a false positive test) is very uncommon,[20] but can result from a hook effect of the measuring tools in extreme cases.[23]

Vegetarianism may contribute to low levels of serum ferritin, with one study finding 40% of vegetarians tested with low serum ferritin levels [24]

Elevated

If ferritin is high, there is iron in excess or else there is an acute inflammatory reaction in which ferritin is mobilized without iron excess. For example, ferritins may be high in infection without signalling body iron overload.

Ferritin is also used as a marker for iron overload disorders, such as hemochromatosis or hemosiderosis. Adult-onset Still's disease, porphyria, and Hemophagocytic lymphohistiocytosis are diseases in which the ferritin level may be abnormally raised.

As ferritin is also an acute-phase reactant, it is often elevated in the course of disease. A normal C-reactive protein can be used to exclude elevated ferritin caused by acute phase reactions.

According to a study of anorexia nervosa patients, ferritin can be elevated during periods of acute malnourishment, perhaps due to iron going into storage as intravascular volume and thus the number of red blood cells falls.[25]

Application

Cavities formed by ferritin and mini-ferritins (Dps) proteins have been successfully used as the reaction chamber for the fabrication of metal nanoparticles (NPs).[26][27][28][29] Protein shells served as a template to restrain particle growth and as a coating to prevent coagulation/aggregation between NPs. Using various sizes of protein shells, various sizes of NPs can be easily synthesized for chemical, physical and bio-medical applications

See also

References

  1. ^ ; Granier T, Langlois d'Estaintot B, Gallois B, Chevalier JM, Précigoux G, Santambrogio P, Arosio P (2003). "Structural description of the active sites of mouse L-chain ferritin at 1.2 A resolution". J. Biol. Inorg. Chem. 8 (1–2): 105–11. doi:10.1007/s00775-002-0389-4. PMID 12459904. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ PDB: 1r03​; Langlois d'Estaintot B, Santambrogio P, Granier T, Gallois B, Chevalier JM, Précigoux G, Levi S, Arosio P (2004). "Crystal structure and biochemical properties of the human mitochondrial ferritin and its mutant Ser144Ala". J. Mol. Biol. 340 (2): 277–93. doi:10.1016/j.jmb.2004.04.036. PMID 15201052. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Iron Use and Storage in the Body: Ferritin and Molecular Representations, Rachel Casiday and Regina Frey, Department of Chemistry, Washington University, St. Louis.
  4. ^ a b c d e f Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1146/annurev.bi.56.070187.001445, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1146/annurev.bi.56.070187.001445 instead.
  5. ^ a b c d e f g h Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1016/0162-0134(92)84062-R , please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1016/0162-0134(92)84062-R instead.
  6. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1016/S1096-4959(03)00050-2 , please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1016/S1096-4959(03)00050-2 instead.
  7. ^ Levi S, Corsi B, Bosisio M, Invernizzi R, Volz A, Sanford D, Arosio P, Drysdale J (2001). "A human mitochondrial ferritin encoded by an intronless gene". J. Biol. Chem. 276 (27): 24437–40. doi:10.1074/jbc.C100141200. PMID 11323407. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  8. ^ http://www.rcsb.org/pdb/images/1R03_ram_m_500.pdf
  9. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.fsi.2007.01.013, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.fsi.2007.01.013 instead.
  10. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1080/01904168209362966, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1080/01904168209362966 instead.
  11. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1042/0264-6021:3570241, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1042/0264-6021:3570241 instead.
  12. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1186/1471-2148-7-160 , please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1186/1471-2148-7-160 instead.
  13. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16626988, please use {{cite journal}} with |pmid=16626988 instead.
  14. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/0304-4165(86)90188-1 , please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/0304-4165(86)90188-1 instead.
  15. ^ a b c Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16262999, please use {{cite journal}} with |pmid=16262999 instead.
  16. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1242/jeb.00872, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1242/jeb.00872 instead.
  17. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 11687259, please use {{cite journal}} with |pmid=11687259 instead.
  18. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1007/BF00398988, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1007/BF00398988 instead.
  19. ^ Guyatt G, Patterson C, Ali M, Singer J, Levine M, Turpie I, Meyer R (1990). "Diagnosis of iron-deficiency anemia in the elderly". Am J Med. 88 (3): 205–9. doi:10.1016/0002-9343(90)90143-2. PMID 2178409.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ a b Interpretation of biochemical tests for iron deficiency: diagnostic difficulties related to limitations of individual tests by Frank Firkin and Bryan Rush. Aust Prescr 1997;20:74-6
  21. ^ Ferritin by: Mark Levin, MD, Hematologist and Oncologist, Newark, NJ. Review provided by VeriMed Healthcare Network
  22. ^ Kryger MH, Otake K, Foerster J (2002). "Low body stores of iron and restless legs syndrome: a correctable cause of insomnia in adolescents and teenagers". Sleep Med. 3 (2): 127–32. doi:10.1016/S1389-9457(01)00160-5. PMID 14592231. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  23. ^ Page 341 in: Burnett, David; Crocker, John R. (1999). The Science of Laboratory Diagnosis. ISIS Medical Media. ISBN 1-899066-62-4.{{cite book}}: CS1 maint: multiple names: authors list (link)
  24. ^ W Pongstaporn, A Bunyaratavej (1999). "Hematological parameters, ferritin and vitamin B12 in vegetarians". J Med Assoc Thai. 82 (3): 304–11. PMID 10410487. {{cite journal}}: Unknown parameter |month= ignored (help)
  25. ^ Kennedy A, Kohn M, Lammi A, Clarke S (2004). "Iron status and haematological changes in adolescent female inpatients with anorexia nervosa". J Paediatr Child Health. 40 (8): 430–2. doi:10.1111/j.1440-1754.2004.00432.x. PMID 15265182.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1021/ja910918b, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1021/ja910918b instead. Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 20170158, please use {{cite journal}} with |pmid=20170158 instead.
  27. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1021/ja0655690, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1021/ja0655690 instead. Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17177411, please use {{cite journal}} with |pmid=17177411 instead.
  28. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1002/smll.200700199, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1002/smll.200700199 instead. Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17768776, please use {{cite journal}} with |pmid=17768776 instead.
  29. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1002/anie.200353436, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1002/anie.200353436 instead. Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15127443, please use {{cite journal}} with |pmid=15127443 instead.
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